What’s The Reason…. Herbal medicines contain a large variety of different compounds. Several of these may have biological activity, but there is a significant risk of side effects and toxicity. The active principle present in small amount, so herbals are expected to be less active than pure compound. Herbal medicines may be interacting with prescribed medicines and there is no regulations or control of this matter and their uses. BUT IT IS AN IMPORTANT LEAD TO DISCOVER AND DESIGN NEW DRUGS.
For Example… Not All Ginseng Is The Same: Rg1 (sterol ginsenoside) Rb1 (sterol ginsenoside) Glucocorticoid receptor Estrogen receptor upregulates a growth receptor different pathway stimulates blood vessel growth inhibits blood vessel growth BUT IT IS AN IMPORTANT LEAD TO DISCOVER AND DESIGN NEW DRUGS
Common Procedure… Marketing 1 to 2 Years Approval Process 3 to 4 Years Clinical Trials 5 to 6 Years Development 3 to 9 Years Research Average 9 to 15 Years…!!
Time is money …..! Cost control by time-oriented development 1 year 1000.000.000 $ 1 month 83.333.774 $ 1 week 19.230.770 $ 1 day 2.739.726 $ 1 hour 114.120 $ 1 minute 1.902 $ 1 second 31,70 $ By accelerated development saved $:
Basic Steps…Chemical Library…Selection of Hits….!! Time andLead Finding Procedure…!! Money….!!!Screening And Structure Illucidation…!Preclinical studies…!!Drug Discovery…!!Clinical Trials,development…!!
New Drug Discovery From Natural Products….Pre knowledge…Collect source..Crude Extracts..Screening…Separation: HPLC,HPTLC,GC…Library.…Finding Lead Molecule…Structure Identification…New Drug Discovery And Development…Clinical Trials .. Phase 1,2,3Approval Procedure.. Marketing…Phase 4
We Need…. Cost control by time-oriented development By accelerated development saved $:
Finding drugs…….. LEAD OPTIMIZATION HITS-TO-LEAD It is necessary toIDENTIFYING HITS optimize the leads The hits are properties: i.e. further examined toxicity, potency, in order to find binding strength,AT This Stage A Lot ... Of Compounds Are some Tested Against The promising drug These Target Protein. candidates – the modifications Compounds Showing so-called leads. results in 10-500 Chemical Activity Typically 1-3 lead lead variations Against The Target sent for pre-Are Promoted To Hits. compound series are found. clinical testing.. Screening A Library With E.G.1,000,000 CompoundsMay Result In 100-500 Hits.
In Vivo…Study…..IN VIVO TESTS• More expensive• May cause suffering to animals• Results may be clouded by interference with other biological systems About 2.6m animals/y used in procedures in UK (11.6m in Europe)
Methods… High Throughput Screening used to search large compound librariesIDENTIFYING HITS · Molecular Docking · QSAR · Pharmacophore Mapping These methods can be used for Virtual Screening. High Throughput Screening for validation runs. Hits-To-Lead Laboratory experiments for confirmation and investigation of binding pro. · Molecular Docking · QSAR · Pharmacophore Mapping LEAD Laboratory experiments for testing the optimized leads.OPTIMIZATION ·
Three must…………………. QSAR Basic conceptsHTS Combinatorial Chemistry
What Is HTS ? Biochemical target Test many compounds Compounds with desired effect on target = Hit OR Hit directly Hit providesused as structure forchemical chemists to beginprobe to study developing a drugtarget or other product
HTS and Technology…..RoboticsMiniaturizationSophisticated Assay ChemistrySophisticated Software and Database
What is QSAR?A QSAR is a mathematical relationshipbetween a biological activity of amolecular system and its geometricand chemical characteristics.QSAR attempts to find consistentrelationship between biological activityand molecular properties, so that these“rules” can be used to evaluate theactivity of new compounds.
Why QSAR?The number of compounds required forsynthesis in order to place 10 differentgroups in 4 positions of benzene ring is 104Solution: synthesize a small number ofcompounds and from their data derive rulesto predict the biological activity of othercompounds.
Compounds + biologicalactivity QSAR New compounds with improved biological activity
For Example…. hydrophobic (blue) and hydrophilic (red) surface area of diazepam.
Few Examples….. O CH3 O CH3 H OH H3C H3C H OH O O O HO H O H3C OH OH O OH CH3 Digitoxin CH3 H OH H3C H3C H OH O O O HO H H3C OH OH Digoxin
OCH3 OCH3 H OH H N H N OH N H N Quinidine QuinineMeO N N H H H O H OCH3 MeOOC O OCH3 OCH3 Reserpine OCH3
HO O HO _ COO O OH RH3C H3C O O CH3 CH3 CH3 CH3 R HO Mevastatin R1 = R2 = H Pravastatin Lovastatin R1 = H; R2 = CH3 Simvastain R1 = R2 = CH3
O O O O O O CH3 * OH O OH OH Warfarin Dicoumarol _ _ _ _ CH2OSO3 COO CH2OH CH2OSO3 CH2OSO3 O O O O_ O O_ O OH OH OH COO OH COO OH OH OHO O O O O O O _ _ _ _ NHSO3 OH NHSO3 OSO3 NHCOCH3 OH NHSO3 Heparin
So….It’s not END of an ERA but…..ENDLESS FRONTIER….!!!
LOGO www.themegallery.com Add your company slogan